The herpes simplex viruses (HSV) are a group of about 100 different double-stranded DNA animal viruses. At least seven are known to be pathogenic to humans and are known as human herpes viruses or HHV. HHV include herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2), varicella zoster virus (VSV or HHV3, which causes chickenpox), cytomegalovirus (HCMV), human herpesvirus type 6 and type 7 (HHV-6 and HHV-7) and Epstein-Barr virus (EBV or HHV4 which causes infectious mononucleosis). Infections by these viruses are among the most common and easily transmitted viral infections, afflicting greater than one million individuals each year in the United States. The hallmark of herpes virus infections is latency. The site of latency is the dorsal root ganglia or the sacral ganglia. Here the virus remains latent and can be reactivated under various conditions of stress. See, for example, B. Roizman et al., Am. Rev. Microbiol., 41, 543 (1987); B. Roizman et al., xe2x80x9cHerpes Simplex and Their Replicationxe2x80x9d, B. Fields, ed., Virology, Raven Press, NY (2d ed., 1990) at pp. 1795-1841; A. H. Haase et al., Viral Pathogenesis, N. Nathanson, ed., Lippincott-Raven (1996) at pp. 465-506.
HSV-1 mainly affects areas above the waist and is most common in children between the ages of one and five. HSV-2 is primarily a sexually transmitted virus affecting the genital areas, sacrum and buttocks. These two types can infect any mucutaneous surface or visceral site and produce clinically indistinguishable lesions. The degree of infection greatly varies from patient to patient, however, those with T-cell defects experience more frequent and severe HSV infections (D. M. Arbesfeld et al., Am. Family Physician, 43, 1655 (1991)).
Numerous treatments for HSV infections have been tried and none have been entirely satisfactory. Chemotherapy (topical or systemic) for HSV infection has included the use of idoxuridine, trifluorothymidine, adenine arabinoside (ara-A), acyclovir, bromovinyl deoxyuridine, foscarnet, and other acyclic nucleoside analogues. Among all the anti-HSV agents, acyclovir (ACV) was the first genuinely selective agent. It profoundly affects viral DNA polymerase function through obligatory chain termination and competitive inhibition. See B. Beam, Postgrad. Med., 77, 297 (1983). The poor absorption rate and pharmacokinetics of acyclovir have been overcome to some extent by the use of prodrugs like valaciclovir and penciclovir in treating infected individuals. However, many HSV-1 and HSV-2 strains have produced mutants that are resistant to ACV. Also, drugs such as ACV require the virus to be actively multiplying and are not active when the virus is latent. The greatest difficulty in finding antiviral compounds is due to the requirement that the active compound must act on virus within a host cell without causing damage to the host cell (A. Chatos et al., Virol., 180, 793 (1991)).
U.S. Pat. No. 5,750,578, issued May 12, 1998, discloses that betulin and certain specific analogs thereof possess antiviral activity. However, there is a continuing need for additional antiviral and antibacterial agents, useful to treat herpes viruses.
The present invention provides a therapeutic method for treating a human afflicted with herpesvirus infection comprising administering to said human an effective anti-viral amount of a compound of formula (I): 
wherein
one of R1 and R2 is xe2x80x94Oxe2x80x94Y and the other is hydrogen or (C1-C6)alkyl optionally substituted by hydroxy, (C1-C6)alkoxy, halo, halo(C1-C6)alkoxy or NRjRk wherein Rj and Rk are independently H, (C1-C6)alkyl or (C1-C6)alkonyl; or R1 and R2 together are oxo (xe2x95x90O);
R3 is hydrogen, halo, carboxy, mercapto, (C1-C6)alkyl, (C3-C8)cycloalkyl, or xe2x80x94Oxe2x80x94Y;
R4 and R5 are each independently hydrogen, (C1-C6)alkyl, or hydroxy(C1-C6)alkyl;
R6 is hydrogen or is absent when the adjacentxe2x80x94is a bond;
R7 is hydrogen or (C1-C6)alkyl;
R8 is hydrogen, (C1-C6)alkyl, or hydroxy(C1-C6)alkyl and R11, is hydrogen, (C1-C6)alkyl, carboxy, or hydroxy(C1-C6)alkyl; or R8 and R11 together are xe2x80x94Oxe2x80x94C(xe2x95x90X)xe2x80x94;
R9 and R10, are each independently hydrogen or (C1-C6)alkyl;
each of the bonds represented byxe2x80x94is independently absent or is present;
X is two hydrogens, oxo (xe2x95x90O) or thioxo (xe2x95x90S);
each Y is independently H, aryl, P(O)(C)2, (C3-C8)cycloalkyl, adamantyl, xe2x80x94SO2Ra Oxe2x95x90P(Rb)2, Oxe2x95x90P(Rc)2OP(O)(Rd)xe2x80x94, Si(Re)3, tetrahydropyran-2-yl, an amino acid, a peptide, a glycoside, or a 1 to 10 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 heteroatoms selected from non-peroxide oxy, thio, and xe2x80x94N(Rf)xe2x80x94; wherein said chain may optionally be substituted on carbon with 1, 2, 3, or 4 oxo (xe2x95x90O), hydroxy, carboxy, halo, mercapto, nitro, xe2x80x94N(Rg)(Rh), (C3-C8)cycloalkyl, (C3-C8)cycloalkyloxy, aryl, aryloxy, adamantyl, adamantyloxy, hydroxyamino, trifluoroacetylamino, a glycoside, an amino acid, or a peptide; and wherein said chain may optionally be saturated or unsaturated (e.g. containing one, two, three or more, double or triple bonds);
Ra is (C1-C6)alkyl or aryl;
Rb, Rc, and Rd are each independently hydroxy, (C1-C6)alkoxy, hydroxy(C2-C6)alkoxy, adamantyloxy, adamantyl(C1-C6)alkoxy, norbomyloxy, 1,1-di(hydroxymethyl)-2-hydroxyethoxy, carboxy(C1-C6)alkoxy, 2,3-epoxypropyloxy, benzyloxy, (C3-C8)cycloalkyloxy, NRxRy, or aryloxy;
Re is H, aryl or (C1-C6)alkyl;
Rf is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl;
Rg and Rh are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, adamantyl, adamantyl(C1-C6)alkyl, amino(C1-C6)alkyl, aminosulfonyl, (C1-C6)alkanoyl, aryl and benzyl; or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino radical; and
Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, aryl or benzyl;
wherein each aryl of Y, Raxe2x80x94Rd, Rgxe2x80x94Rh, Rx, and Ry may optionally be substituted by 1, 2, or 3 aminosulfonyl, carboxy, NRiRj, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, trifluoromethoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, or (C1-C6)alkanoyloxy; wherein Ri and Rj are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl, or benzyl;
or a pharmaceutically acceptable salt thereof.
The invention also provides novel compounds of formula I, as well as intermediates and processes useful for preparing compounds of formula I. The compound of formula (I): 3xcex2-hydroxy-19xcex1H-19,28-epoxy-oleanane is known as allobetulin. Additionally, the compounds uvaol, ursolic acid, and hederin hydrate are known compounds of formula I (see FIG. I). Accordingly, compounds of the formula I preferably exclude allobetulin, uvaol, ursolic acid, and hederin hydrate. Compounds of the invention also preferably exclude the corresponding acetates of these alcohols.
J. Schmidt and S. Huneck Organic Mass Spectrometry, 1979, 14, 646-655 disclose the mass spectrometry behavior of certain compounds of formula (I). Accordingly, compounds of the invention preferably exclude:
a) a compound of formula (I) wherein: R1 is OH; when R2 is hydrogen, R3 is hydrogen, R4 is methyl, R5 is methyl, R6 is hydrogen, R7 is hydrogen, R9 is methyl, R10 is methyl, the bond at the 1 and 2 positions represented by --- is present or absent, the bond at the 12 and 13 positions represented by --- is absent, and R8 and R11 together are xe2x80x94O-CH2xe2x80x94.
b) a compound of formula (I) wherein: R1 is hydroxy or acetoxy;
when R2 is hydrogen, R3 is hydrogen, R4 is methyl, R5 is methyl, R6 is hydrogen, R7 is hydrogen, R9 is methyl, R10 is methyl, the bond at the 1 and 2 positions represented byxe2x80x94is present or absent, the bond at the 12 and 13 positions represented byxe2x80x94is absent, and R8 and R11 together are xe2x80x94Oxe2x80x94CH2xe2x80x94; and
c) a compound of formula (I) wherein: R1 and R2 together are oxo;
when R3 is hydrogen, R4 is methyl, R5 is methyl, R6 is hydrogen, R7 is hydrogen, R9 is methyl, R10 is methyl, the bond at the 1 and 2 positions represented by --- is present or absent, the bond at the 12 and 13 positions represented by --- is absent, and R8 and R11 together are xe2x80x94Oxe2x80x94CH2.
L. E. Odinokova et al. Khim. Prir. Soedin., 1961, 2, 182-187 disclose specific allobetulin derivatives. Accordingly compounds of the invention preferably exclude compounds of formula (I) wherein R1 is xe2x80x94Oxe2x80x94Y, Y is: 
and each Z is hydrogen or acyl; when R2 is hydrogen, R3 is hydrogen, R4 is methyl, R5 is methyl, R6 is hydrogen, R7 is hydrogen, R9 is methyl, R10 is methyl, the bond at the 1 and 2 positions represented by --- is absent, the bond at the 12 and 13 positions represented by --- is absent, and R8 and R11 together are xe2x80x94Oxe2x80x94CH2xe2x80x94.
A. Patra and S. Chaudhuri, Indian J. Chemistry, 1988, 27B, 170-172 disclose the conversion of 3-acetylbetulinic acid to 3-acetylbetulinic lactone.
Accordingly, compounds of the invention preferably exclude a compound of formula (I) wherein: R1 is acetoxy; when R2 is hydrogen, R3 is hydrogen, R4 is methyl, R5 is methyl, R6 is hydrogen, R7 is hydrogen, R9 is methyl, R10 is methyl, the bond at the 1 and 2 positions represented by --- is absent, the bond at the 12 and 13 positions represented by --- is absent, and R8 and R11 together are xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94.
L. A. Baltina et al., Russian Journal of Bioorganic Chemistry, 1997, 23, 745-750 disclose the synthesis of certain L-Rhamnal derivatives of formula (I). Accordingly compounds of the invention preferably exclude compounds of formula (I) wherein R1 is: 
wherein each Z is hydrogen or acetyl; when R2 is hydrogen, R3 is hydrogen, R4 is methyl, R5 is methyl, R6 is hydrogen, R7 is hydrogen, R9 is methyl, R10 is methyl, the bond at the 1 and 2 positions represented by --- is absent, the bond at the 12 and 13 positions represented by --- is absent, and R8 and R11 together are xe2x80x94Oxe2x80x94CH2xe2x80x94.
F. N. Lugemwa et al., J. Agric. Food Chem. 1990, 36, 493-496 disclose the preparation and biological screening of certain compounds of formula (I). Accordingly, the compounds of the invention preferably exclude a compound of formula (I) wherein: R1 and R2 together are oxo; when R3 is hydroxy, R4 is methyl, R5 is methyl, R6 is hydrogen, R7 is hydrogen, R9 is methyl, R10 is methyl, the bond at the 1 and 2 positions represented by --- is present, the bond at the 12 and 13 positions represented by --- is absent, and R8 and R11 together are xe2x80x94Oxe2x80x94CH2.
The compounds of the invention also preferably exclude a compound of formula (I) wherein R1 and R2 tog ether are oxo; when R3 is: 
and each Z is hydrogen or acyl; R4 is methyl, R5 is methyl, R6 is hydrogen, R7 is hydrogen, R9 is methyl, R10 is methyl, the bond at the 1 and 2 positions represented by --- is present, the bond at the 12 and 13 positions represented by --- is absent, and R8 and R11 together are xe2x80x94Oxe2x80x94CH2.
The invention also provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition of the invention excludes compounds of formula (I) wherein R1 is: 
wherein each Z is acetyl; when R2 is hydrogen, R3 is hydrogen, R4 is methyl, R5 is methyl, R6 is hydrogen, R7 is hydrogen, R9 is methyl, R10 is methyl, the bond at the 1 and 2 positions represented by --- is absent, the bond at the 12 and 13 positions represented by --- is absent, and R8 and R11 together are xe2x80x94Oxe2x80x94CH2xe2x80x94.
The pharmaceutical composition of the invention also preferably excludes a compound of formula (I) wherein R1 and R2 together are oxo; when R3 is: 
each Z is hydrogen or acyl; R4 is methyl, R5 is methyl, R6 is hydrogen, R7 is hydrogen, R9 is methyl, R10 is methyl, the bond at the 1 and 2 positions represented by --- is present, the bond at the 12 and 13 positions represented by --- is absent, and R8 and R11 together are xe2x80x94Oxe2x80x94CH2.
The pharmaceutical composition of the invention also preferably excludes allobetulin, uvaol, ursolic acid, and hederin hydrate and pharmaceutically acceptable salts thereof; and can also exclude the corresponding acetates of these alcohols.
The invention also provides a compound of formula I for use in medical therapy (preferably for use in treatment of herpesvirus infection), as well as the use of a compound of the invention for the manufacture of a medicament useful for the treatment of herpesvirus infection. Preferably, a compound of formula I for use in medical therapy excludes compounds of formula I that, as disclosed above, can preferably be excluded from the pharmaceutical compositions of the invention.
The compounds of formula (I) may be administered as pharmaceutical compositions, locally or systemically, and are effective to treat (block or inhibit) herpesvirus infections, including active or latent infections. Susceptible herpesvirus infections include HSV-1, HSV-2, VZV, HCMV, HHV-6, HHV-7 or HHV4 (Epstein-Barr virus) infections. Compounds of formula (I) are particularly effective against HSV-1 and HSV-2.